Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis.

While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

Optimized structure of monoubiquitinated FANCD2 (human) at Lys 561: a theoretical approach.

Fanconi anaemia pathway repairs inter-strand cross linking damage (ICL) of the DNA. Monoubiquitination of FANCD2 and FANCI is very crucial for ICL repairing. In this work we have tried to understand the monoubiquitinated FANCD2 structure, which facilitates the FANCD2 for binding the damage part of the chromatin. Crystal structure of the monoubiquitinated FANCD2 alone is not available, therefore we have modelled the optimized structure of the human monoubiquitinated (Lys 561) FANCD2. As there is no suitable software or web server we have developed a method for building up monoubiquitinated product and validated on simplest monoubiquitinated protein, diubiquitin. We have predicted the structure of human monoubiquitinated FANCD2 by using our method and studied the interaction with DNA by docking studies. Molecular Dynamics (MD) simulation has been used to understand the stability of the structure. Large structural differences have been observed between FANCD2 and monoubiquitinated FANCD2. Docking studies with DNA suggest that the binding site varies for the FANCD2 and monoubiquitinated FANCD2.Communicated by Ramaswamy H. Sarma.

Discovery of BMS-986144, a Third-Generation, Pan-Genotype NS3/4A Protease Inhibitor for the Treatment of Hepatitis C Virus Infection.

The discovery of a pan-genotypic hepatitis C virus (HCV) NS3/4A protease inhibitor based on a P1-P3 macrocyclic tripeptide motif is described. The all-carbon tether linking the P1-P3 subsites of 21 is functionalized with alkyl substituents, which are shown to effectively modulate both potency and absorption, distribution, metabolism, and excretion (ADME) properties. The CF3Boc-group that caps the P3 amino moiety was discovered to be an essential contributor to metabolic stability, while positioning a methyl group at the C1 position of the P1' cyclopropyl ring enhanced plasma trough values following oral administration to rats. The C7-fluoro, C6-CD3O substitution pattern of the P2* isoquinoline heterocycle of 21 was essential to securing the targeted potency, pharmacokinetic (PK), and toxicological profiles. The C6-CD3O redirected metabolism away from a problematic pathway, thereby circumventing the time-dependent cytochrome P (CYP) 450 inhibition observed with the C6-CH3O prototype.

Comparative evaluation of predictive value of three caries activity tests-snyder, lactobacillus count and cariostat in mixed dentition children with and without caries.

INTRODUCTION: Dental caries is a disease with multifactorial etiology. Early detection and preventive measures are essential for caries control. Caries activity tests are one of the methods of early detection, but all these are based on microbiological study. AIMS: Compare the sensitivity and specificity of Snyder test (ST), lactobacillus count (LBC) and Cariostat in mixed dentition children with and without caries. MATERIALS AND METHODS: 90 healthy mixed dentition children (79 boys and 11 girls) were selected and were divided into two groups, one with Decayed missing filled teeth (DMFT) 0 and another group with DMFT 3-5. The salivary samples were collected for ST and LBC and plaque samples were collected for Cariostat. Caries activity was assessed. RESULTS: The data obtained were analyzed for sensitivity, specificity, positive predictive value, negative predictive value and over all accuracy. CONCLUSIONS: Our present study showed that the LBC was found to have a higher correlation in caries as the caries increased the count also increased with positive caries activity. A good correlation was found between Snyder and LBC for the caries activity 1, 2 and 3. But no correlation was seen for score 0. To conclude, a combination of all these tests was found to be good for assessing caries risk groups.

Conscious sedation--an artist's science! An Indian experience with midazolam.

The present study was undertaken to evaluate Midazolam as a Paediatric conscious sedative agent for a routine Indian dental setup and to compare its efficacy and safety when administered by intranasal and intramuscular routes, at a dosage of 0.2 mg/kg body weight. The present study was accomplished in two phases: Phase 1: Preliminary dose finding pilot study on 10 children. Phase 2: Single dose, randomized parallel clinical trial on 40 children between the ages of 2 and 5 years. These children were randomly assigned to two groups consisting of 20 subjects each. Group M, received Midazolam intramuscularly, while Group N received Midazolam intranasally. Both the intranasal and intramuscular groups showed highly significant decrease in crying levels, motor movements and sensory perception levels, post-sedation (P P < 0.001). Midazolam could be safely and successfully employed by intranasal and intramuscular routes for Paediatric conscious sedation in a routine dental setup with basic facilities at a dosage of 0.2 mg/ kg body weight. Whenever the clinical situation warrants a faster action, peak and recovery, the intranasal route should be the obvious choice.